ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation

Vliet, Alexander R. van; Chiduza, George N.; Pye, V.E.; Joshi, Dhira; Tito, Stefano De; Jefferies, Harold B.J.; Christodoulou, Evangelos; Roustan, Chloë; Punch, Emma K.; Hervás, Javier H.; O’Reilly, Nicola; Skehel, J. Mark; Cherepanov, Peter; Tooze, Sharon A.

doi:10.1016/j.molcel.2022.10.017

Cited by 66 publications

(84 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that Atg2 and Atg9 physically interact (Gomez-Sanchez et al, 2018), these data are consistent with the notion that the number of Atg2 molecules is physically coupled with the number of trimeric Atg9 complexes in a 1:1 ratio at early phagophores to coordinate PLT with phospholipid scrambling. Indeed, very recent structural analysis described a Atg2-Atg9 complex in mammals (van Vliet et al, 2022). However, following this initial stage, we observed that the number of Atg2 molecules increased to a maximum of 64 ± 23 Atg2 molecules during phagophore expansion (“max”) and then dropped to 38 ± 15 Atg2 molecules at closing or closed autophagosomes (“end”)( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Instead, our data and work from others show that only Atg2-mediated PLT is essential for autophagy in yeast and mammalian cells (Tan and Finkel, 2022; Valverde et al, 2019). The molecular basis for the essential nature of PLT by Atg2 has yet to be defined, but the physical interaction of Atg2 with Atg9 raises the possibility that phospholipid transfer by Atg2 has to be coupled to the scramblase activity of Atg9 (Gomez-Sanchez et al, 2018; Maeda et al, 2020; Matoba et al, 2020; Orii et al, 2021; van Vliet et al, 2022). In this context, it remains to be analyzed whether Vps13 binds to a dedicated scramblase or relies directly or indirectly on Atg9-mediated scrambling within the phagophore membrane.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, this hydrophobic groove displays non-vesicular phospholipid transfer (PLT) activity allowing phospholipids exchange between tethered membranes (Maeda et al, 2019; Osawa et al, 2019; Valverde et al, 2019). At the rim of the phagophore, Atg2 physically interacts with the transmembrane protein Atg9 (Gomez-Sanchez et al, 2018; van Vliet et al, 2022). Atg9 forms a homotrimeric complex with an inherent phospholipid scramblase activity (Ghanbarpour et al, 2021; Guardia et al, 2020; Maeda et al, 2020; Matoba et al, 2020; Orii et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Atg9 forms a homotrimeric complex with an inherent phospholipid scramblase activity (Ghanbarpour et al, 2021; Guardia et al, 2020; Maeda et al, 2020; Matoba et al, 2020; Orii et al, 2021). Interestingly, mammalian ATG2A and ATG9A form a heteromeric complex, in which the opening of the hydrophobic groove of ATG2A aligns with an internal channel of ATG9A implicated in phospholipid scrambling (van Vliet et al, 2022). Thus, this spatial and functional arrangement suggest that Atg2 and Atg9 may constitute a minimal system for non-vesicular transfer and scrambling of phospholipids from the ER into the outer leaflet and equilibration between both leaflets of the phagophore membrane to allow for formation of large autophagosomes.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

Dabrowski

Tulli

Graef

2022

Preprint

View full text Add to dashboard Cite

During autophagy, rapid membrane assembly expands small phagophores into large double-membrane autophagosomes. Theoretical modelling predicts the majority of autophagosomal phospholipids is derived from highly efficient non-vesicular phospholipid transfer (PLT) across phagophore-ER contacts (PERCS). Currently, the phagophore-ER tether Atg2 is the only PLT protein known to drive phagophore expansion in vivo. Here, our quantitative live-cell-imaging analysis reveals poor correlation between duration and size of forming autophagosomes and number of Atg2 molecules at PERCS of starving yeast cells. Strikingly, we find Atg2-mediated PLT is non-rate-limiting for autophagosome biogenesis, because membrane tether and PLT protein Vps13 localizes to the rim and promotes expansion of phagophores in parallel with Atg2. In the absence of Vps13, the number of Atg2 molecules at PERCS determines duration and size of forming autophagosomes with an apparent in vivo transfer rate of ~200 phospholipids per Atg2 molecule and second. We propose conserved PLT proteins cooperate in channeling phospholipids across organelle contact sites for non-rate-limiting membrane assembly during autophagosome biogenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

Dabrowski

Tulli

Graef

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In vivo, Atg2 is recruited to the phagophore via coincidence binding to PtdIns3P and Atg9, which concentrates on high curvature membrane regions such as the extremities of the phagophore [ 52 ]. Atg2 binding (via its C-terminal region) to Atg9 induces the subsequent recruitment of Atg18, which bind to both Atg2 and PtdIns3P ( Figure 3 A) [ 52 , 62 , 63 ]. The N-terminal domain of Atg2, in contrast, appears to be responsible for its interaction with the ER [ 57 ], but it remains enigmatic which ERES components bind to ATG2 proteins.…”

Section: Mcss During Autophagosome Biogenesismentioning

confidence: 99%

Membrane Contact Sites in Autophagy

Zwilling

Reggiori

2022

Cells

View full text Add to dashboard Cite

Eukaryotes utilize different communication strategies to coordinate processes between different cellular compartments either indirectly, through vesicular transport, or directly, via membrane contact sites (MCSs). MCSs have been implicated in lipid metabolism, calcium signaling and the regulation of organelle biogenesis in various cell types. Several studies have shown that MCSs play a crucial role in the regulation of macroautophagy, an intracellular catabolic transport route that is characterized by the delivery of cargoes (proteins, protein complexes or aggregates, organelles and pathogens) to yeast and plant vacuoles or mammalian lysosomes, for their degradation and recycling into basic metabolites. Macroautophagy is characterized by the de novo formation of double-membrane vesicles called autophagosomes, and their biogenesis requires an enormous amount of lipids. MCSs appear to have a central role in this supply, as well as in the organization of the autophagy-related (ATG) machinery. In this review, we will summarize the evidence for the participation of specific MCSs in autophagosome formation, with a focus on the budding yeast and mammalian systems.

show abstract

Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis

et al. 2023

Self Cite

View full text Add to dashboard Cite

Autophagy is a highly conserved intracellular pathway that is essential for survival in all eukaryotes. In healthy cells, autophagy is used to remove damaged intracellular components, which can be as simple as unfolded proteins or as complex as whole mitochondria. Once the damaged component is captured, the autophagosome engulfs it and closes, isolating the content from the cytoplasm. The autophagosome then fuses with the late endosome and/or lysosome to deliver its content to the lysosome for degradation. Formation of the autophagosome, sequestration or capture of content, and closure all require the ATG proteins, which constitute the essential core autophagy protein machinery. This brief ‘nutshell’ will highlight recent data revealing the importance of small membrane‐associated domains in the ATG proteins. In particular, recent findings from two parallel studies reveal the unexpected key role of α‐helical structures in the ATG8 conjugation machinery and ATG8s. These studies illustrate how unique membrane association modules can control the formation of autophagosomes.

show abstract

ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation

Cited by 66 publications

References 58 publications

Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

Membrane Contact Sites in Autophagy

Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis

Contact Info

Product

Resources

About